Increased susceptibility to streptozotocin-induced beta-cell apoptosis and delayed autoimmune diabetes in alkylpurine-DNA-N-glycosylase-deficient mice

Cardinal, John W., Margison, Geoffrey P., Mynett, Kurt J., Yates, Allen P., Cameron, Donald P. and Elder, Rhoderick H. (2001) Increased susceptibility to streptozotocin-induced beta-cell apoptosis and delayed autoimmune diabetes in alkylpurine-DNA-N-glycosylase-deficient mice. Molecular And Cellular Biology, 21 16: 5605-5613. doi:10.1128/MCB.21.16.5605-5613.2001

Attached Files (Some files may be inaccessible until you login with your UQ eSpace credentials)
Name Description MIMEType Size Downloads
UQ60915_OA.pdf Full text (open access) application/pdf 1.52MB 0

Author Cardinal, John W.
Margison, Geoffrey P.
Mynett, Kurt J.
Yates, Allen P.
Cameron, Donald P.
Elder, Rhoderick H.
Title Increased susceptibility to streptozotocin-induced beta-cell apoptosis and delayed autoimmune diabetes in alkylpurine-DNA-N-glycosylase-deficient mice
Journal name Molecular And Cellular Biology   Check publisher's open access policy
ISSN 0270-7306
1098-5549
Publication date 2001
Sub-type Article (original research)
DOI 10.1128/MCB.21.16.5605-5613.2001
Open Access Status File (Publisher version)
Volume 21
Issue 16
Start page 5605
End page 5613
Total pages 9
Place of publication Washington, DC, United States
Publisher American Society for Microbiology
Collection year 2001
Language eng
Abstract Type I diabetes is thought to occur as a result of the loss of insulin-producing pancreatic beta cells by an environmentally triggered autoimmune reaction. In rodent models of diabetes, streptozotocin (STZ), a genotoxic methylating agent that is targeted to the beta cells, is used to trigger the initial cell death. High single doses of STZ cause extensive beta -cell necrosis, while multiple low doses induce limited apoptosis, which elicits an autoimmune reaction that eliminates the remaining cells. We now show that in mice lacking the DNA repair enzyme alkylpurine-DNA-N-glycosylase (APNG), beta -cell necrosis was markedly attenuated after a single dose of STZ. This is most probably due to the reduction in the frequency of base excision repair-induced strand breaks and the consequent activation of poly(ADP-ribose) polymerase (PARP), which results in catastrophic ATP depletion and cell necrosis. Indeed, PARP activity was not induced in A-PNG(-/-) islet cells following treatment with STZ in vitro. However, 48 h after STZ treatment, there was a peak of apoptosis in the beta cells of APNG(-/-) mice. Apoptosis was not observed in PARP-inhibited APNG(+/+) mice, suggesting that apoptotic pathways are activated in the absence of significant numbers of DNA strand breaks. Interestingly, STZ-treated APNG(-/-) mice succumbed to diabetes 8 months after treatment, in contrast to previous work with PARP inhibitors, where a high incidence of beta -cell tumors was observed. In the multiple-low-dose model, STZ induced diabetes in both APNG(-/-) and APNG(-/-) mice; however, the initial peak of apoptosis was 2.5-fold greater in the APNG(-/-) mice. We conclude that APNG substrates are diabetogenic but by different mechanisms according to the status of APNG activity.
Keyword Biochemistry & Molecular Biology
Cell Biology
Poly(adp-ribose) Polymerase Gene
Kappa-b Activation
Pancreatic-islets
Nitric-oxide
Mouse Model
Nicotinamide
Induction
Insulin
Death
Carcinogenesis
Q-Index Code C1

Document type: Journal Article
Sub-type: Article (original research)
Collection: School of Biomedical Sciences Publications
 
Versions
Version Filter Type
Citation counts: TR Web of Science Citation Count  Cited 35 times in Thomson Reuters Web of Science Article | Citations
Scopus Citation Count Cited 41 times in Scopus Article | Citations
Google Scholar Search Google Scholar
Created: Tue, 14 Aug 2007, 16:51:51 EST